3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (Formula I) is widely used for production of fungicides such as Isopyrazam and Sedaxane.
Annual production of fungicides exceeds 30,000 metric tons. Any improvement in cost efficiency or waste reduction, even if small, has large economic and environmental benefits.

A synthesis of Formula I was first published in U.S. Pat. No. 5,093,347 and consisted of four steps.
Alkyl difluoroacetate of Formula II reacts with alkyl acetate of Formula III via Claisen ester condensation to give the enolate salt of alkyl difluoroacetoacetate of Formula IV.

The enolate salt of Formula IV is then acidified to release the free alkyl difluoroacetoacetate of Formula V.

The alkyl difluoroacetoacetate of Formula V is coupled with trialkyl orthoformate in the presence of excess acetyl anhydride to provide the intermediate of Formula VI.

The intermediate of Formula VI is then reacted with methylhydrazine hydrate in the presence of NaOH/KOH to form the alkyl ester of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of Formula VII.

Basic hydrolysis of the alkyl ester of Formula VII, followed by acidification, results in the title product of Formula I.

Many other patent and non-patent publications have reported synthetic methods for preparing alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate of Formula VII. But, most of the published synthetic routes are the same as the original route in principal. A great deal of effort has focused on improving the reaction conditions and/or work up methods.
For decades, the work up process of the Claisen condensation has been unchanged. After the Claisen condensation is finished, a protic acid in aqueous solution, such as HCl, HBr, H2SO4, H3PO4, or acetic acid, is added to neutralize the enolate salt of the ester. The organic phase is then separated from the aqueous phase, the aqueous phase is extracted with organic solvent 2-3 times, the combined organic phases are washed with water and/or brine, the organic solution is dried over a drying agent, then filtered and concentrated to remove the organic solvent and low boiling point impurities to obtain the crude alkyl difluoroacetoacetate. The crude alkyl difluoroacetoacetate is then purified by high vacuum distillation.
Separating the organic phase from the aqueous phase is difficult due to the presence of the highly soluble alkyl alcohol generated in the condensation. The alkyl alcohol interferes with the two phase separation process.
Residual water in the product, free alkyl difluoroacetoacetate of Formula V, is also detrimental to the next coupling reaction. To completely remove the residual water from the organic phase, high vacuum and high heat must be applied during fractional distillation. For an industrial scale reaction this step of the synthesis requires 20-30 hours. The whole process of extraction, drying, evaporation and fractional vacuum distillation for an industrial scale synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid requires several working days to finish. Additionally, the huge amount of used and contaminated drying agents cannot be easily treated and disposed.
An additional shortfall of this procedure is the decomposition of the desired product (Formula V) during the distillation under high temperature. It is well known that hydrolysis followed by decarboxylation of the β-keto-esters occurs to yield a ketone, an alcohol, and carbon dioxide.

The inefficiencies in the alkyl difluoroacetoacetate (Formula V) synthesis can reduce product yield by 10-15%, reduce the facility's productivity, and generate huge amounts of drying agent waste.
WO 2009/106619 describes an improved work up method to avoid the difficulties in separation and distillation for the process described above. In the WO 2009/106619 method after the Claisen condensation is complete, an acid, such as concentrated H2SO4, formic acid, p-toluenesulfonic acid, or methanesulfonic acid, is added to the reaction mixture to acidify the basic enolate salt, and to release free alkyl difluoroacetoacetate. Alternatively, a gaseous acid, such as HCl gas or HBr gas is introduced into the reaction mixture accompanied by a small amount of water. The pressurized HCl or HBr gas is bubbled into the reaction mixture for several hours to release free alkyl difluoroacetoacetate. This procedure has the disadvantage of producing a precipitated solid, as NaCl, Na2SO4, sodium methylsulfonate, or sodium formate, which must be removed.
Though the WO 2009/106619 method provides an improvement in the Claisen condensation reaction workup, which increases yield, the method has obvious disadvantages. The removal of the resultant salts, such as NaCl, Na2SO4, sodium methylsulfonate, and sodium formate is time consuming. The filtered cake is washed four times with a large volume of ethyl acetate, increasing the chemical cost. Since excess HCl gas is introduced, the excess HCl gas must be removed, for example by vacuum pump. Due to the highly corrosive nature of HCl, extra costs must be incurred to protect the safety of manufacturing personnel and insure the continued functioning of the manufacturing facility. For example, all facility equipment must be fitted with corrosion resistant materials that meet corrosion resistance standards.
WO 2011/113789 provides a minor improvement over WO 2009/106619. In the WO 2011/113789 method after the Claisen condensation is complete, the pressurized HCl gas is introduced for several hours without the addition of water. The resulting sodium chloride is not removed. The whole reaction mixture including the product, impurities, and the inorganic solid in a mixture of ethyl acetate and ethanol, is then directly transferred into another reactor for the next step. The transfer of the mixture, which is very viscous, is difficult. Moreover, the disadvantages described for the WO 2009/106619 mentioned above are still present.
To date, all reported 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid synthesis methods proceed via a Claisen condensation, and require removing alkyl alcohols resulting from the reaction and excess alkyl acetate starting material by distillation after acidification. As discussed, this procedure has a number of disadvantages including waste generation, suboptimal yield, and long reaction workup time.
There are also considerable disadvantages to the drying methods reported for preparing fluoro acetoacetate for the subsequent coupling reaction. US 2012-0302608 uses a large amount of 4 Å molecular sieve powder to absorb the water. Other reported methods use Drierite (anhydrous calcium sulfate) to absorb residual water. Another approach employs a large volume of solvents such as ethyl acetate, cyclohexane, petroleum ether, or toluene for azeotropic distillation to drive the water out of the system. All these methods increase the chemical cost and are time consuming. None are particularly effective as 0.5-3.0% v/v residual water remains for each previously reported drying method.
U.S. Pat. No. 7,863,460 provides a method for selectively producing high purity ethyl 3-trifluoromethyl 1H-pyrazole-4-carboxylate in a two phase system in which the reaction is promoted by NaOH or KOH. After the reaction is complete the two phases are separated and the aqueous phase is extracted. The combined organic phases are dried over drying agent, and after filtration the filtrate is evaporated to give the crude ester as a white solid. The ester of Formula VII is finally hydrolyzed by NaOH/KOH aqueous solution, followed by acidification with HCl/H2O to produce the final product of Formula I. A disadvantage of this process is the simultaneous formation of the regioisomer of Formula X, which must be removed by additional crystallizations.

There remains a need for a 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid synthesis with a highly efficient Claisen condensation reaction workup, which has advantages of high yield, simple and safe operation, short workup time, and no or minimal chemical waste generation. There also remains the need for a highly effective drying method to remove residual water prior to the alkyl orthoformate coupling and a highly efficient ring closure system. The method described in this disclosure meets all these objectives and provides additional advantages.